The neurotoxicity of excitatory neurotransmitters has led to the development of the excitotoxicity hypothesis for neuronal cell death. [For review see, B. Engelsen, "Neurotransmitter Glutamate: its Clinical Importance", Acta Neurol Scand, 1986, 74:337-355; R. Schwarcz and B. Meldrum, "Excitatory Aminoacid Antagonists Provide a Therapeutic Approach to Neurologic Disorders", Lancet, 1985, 8447: 140-143] According to this hypothesis, sustained depolarization of neurons expressing receptors for excitatory amino acids ultimately leads to irreversible damage and their death. Sustained depolarizations may arise from several different mechanisms including increased release of glutamate, decreased reuptake of glutamate, or alterations in the characteristics of the glutamate receptor. The presence of one or more of these mechanisms in an individual may result in neurodegeneration and the onset of clinical symptons. Several neurodegenerative disorders have been identified which are associated with one or more of the above alterations of glutamate activity. [B. Engelsen, "Neurotransmitter Glutamate: its Clinical Importance", Acta Neurol Scand, 1986, 74:337-355. The contents of this reference are herein incorporated by reference].
As toxicity has been associated with sustained depolarization through receptor activation, the predominant approach towards preventing the neurotoxic effect of neuroexcitatory neurotransmitters has been to develop effective antagonists for neuroexcitatory receptors. [R. Schwarcz and B. Meldrum, "Excitatory Aminoacid Antagonists Provide a Therapeutic Approach to Neurologic Disorders," Lancet, 1985, 8447: 140-143; S. M. Ross, M. Seelig, and P. Spencer, "Specific Antagonism of Excitotoxic action of `Uncommon` amino acids in Organotypic Mouse Cortical cultures," Brain Res., 1987, 425:120-127] An example of this approach is the study of Guam ALS. The neurotoxic acitivity of beta-N-Methylamino-L-alanin (BMAA) and beta-N-oxalylamino-L-alanine (BOAA), compounds which are present in seeds of Cycas circinalis and Lathyrus sativus, respectively and which have been implicated in the eitology of Guam ALS, have been selectively antagonized in a concentration dependent manner by compounds which are specific antagonists of glutamate receptor sites. Thus, the development of specifically designed antagonists, especially those which block NMDA glutamate receptors, has been suggested to be "[o]ne of the most promising concepts concerning a rational treatment of neurodegenerative disorders[.]" [R. Schwarcz and B. Meldrum, "Excitatory Aminoacid Antagonists Provide a Therapeutic Approach to Neurologic Disorders, Lancet, 1985, 8447: 140-143 ]
Amyotrophic lateral sclerosis is a relentlessly progressive neurological disorder that is manifested primarily by muscle weakness, wasting, and spasticity, usually resulting in death from debilitating disease in 2-5 years [Brain, The Lord, Croft P., Wilkinson M. The course and outcome of motor neuron disease. In: Norris FH, Jurland LT, eds. Motor Neuron Diseases. New York: Grune and Stratton, 1967:22]. No treatment is known at present that can influence the course of the disease.
The cause of ALS is unknown. Recent studies [Plaitakis A., Carosoio JT. "Abnormal glutamate metabolism in amyotrophic lateral sclerosis," Ann Neurol 1987. 22:575-579], however, have shown that the metabolism of the neuroexcitotoxic amino acid glutamate [Olney JW. "Neurotoxicity of excitatory amino acids," In: McGeer EG, Olney JW, McGeer PL eds. Kainic Acid as a Tool in Neurobiology. New York: Raven Press, 1978:95-121] is altered in this disorder and that the possibility exists that neurodegenerative processes in ALS may be mediated by neuroexcitotoxic mechanisms [Plaitakis A., Caroscio JT. "Abnormal glutamate metabolism in amyotrophic lateral sclerosis," Ann Neurol 1987. 22:575-579; Spencer PS, Nunn PB, Hugon J. et al. "Guam amyotrophic lateral sclerosis-Parkinsonism-dementia linked to a plant excitant neurotoxin," Science, 1987, 237:517-522].
Abnormal glutamate metabolism has, in addition to ALS, been shown to occur in patients with late-onset multi-system atrophic disorders associated with decreased activity of the enzyme glutamate dehydrogenase (GDH). [Plaitakis A., Berl S., Yahr MD. "Abnormal glutamate metabolism in an adult-onset neurological disorder," Science, 1982, 216:193-196]. Some of these patients with decreased GDH activity have been described to show predominant motor neuron involvement, or atypical ALS. [Plaitakis A., Berl S., Yahr MD. "Neurological disorders associated with deficiency of glutamate dehydrogenase," Ann. Neurol. 1984, 15:144-153]. GDH is particularly important in the biology of the nervous system and the integrity of motor neurons. GDH can be activated by the branched chain amino acids (BCAA) L-leucine and L-isoleucine [Yielding KL, Tomkins GM. "An effect of L-leucine and other essential amino acids on the structure and activity of glutamate dehydrogenase," Proc. Natl. Acad. Sci. USA, 1961, 47:983].
This invention relates to the use of dietary supplementation with branched chain amino acids (BCAAs) L-leucine, L-isoleucine and L-valine to benefit patients with idiopathic ALS. These compounds have been shown to allosterically activate, in vitro, glutamate dehydrogenase [Yielding KL, Tomkins GM. "An Effect of L-leucine and other essential amino acids on the structure and activity of glutamate dehydrogenase," Proc. Natl. Acad. Sci. USA, 1961, 47:983] and modify the metabolism of glutamate [Dennis S., Clark, J. B. "The synthesis of glutamate by rat brain mitochondria," J. Neurochem 1986; 46:1811-1819], which is reported to be altered in ALS [Plaitakis A., Caroscio J. T. "Abnormal glutamate metabolism in amyotrophic lateral sclerosis," Ann Neurol 1987. 22:575-579].
Evidence of the novelty of the treatments and compositions disclosed by this invention is indicated by a recent report which describes the use of L-threonine to modify the progression of ALS. [B. M. Patten and L. M. Klein, "L-Threonine and the Modification of ALS," Neurology, 1988, 38 (Suppl 1):354-355] To substitute for L-threonine, L-leucine or L-isoleucine were used as placebos. Patients treated with placebo were reported to "revert to previous status."